Gene modification may benefit the therapy of human neurodegenerative conditions such as Alzheimer's disease (AD) and Parkinson's disease (PD). Over the last 10 years, we have demonstrated that ex vivo NGF gene transfer to the primate brain can prevent cholinergic neuronal death, and reverse spontaneous cholinergic neuronal decline with aging. These findings have led to the first clinical trial of gene therapy to treat an age-related neurodegenerative disorder. While our ex vivo clinical trial of NGF gene delivery will test the hypothesis that NGF delivery to cholinergic neurons may delay progression in AD, ex vivo gene delivery is generally a cumbersome and expensive approach for gene therapy in the CNS. In vivo gene therapy, wherein vectors capable of infecting non-dividing cells are directly injected into the brain, offers a simpler and more realistic approach to gene delivery in large numbers of people. Substantial advances in the field of in vivo vectorology have been made over the past 5 years, with recent reports of sustained and safe gene expression in both rodent and primate models of neurological disease. Thus, this project will determine whether in vivo gene therapy can delivery therapeutic molecules to the adult primate brain in a safe and effective manner to prevent neuronal degeneration and ameliorate cognitive decline. Further, we will characterize effects of aging on cognition to generate novel information regarding mechanisms of neural dysfunction with primate aging, and the sensitivity of this dysfunction to growth factor gene delivery. Finally, we aim to develop a primate in vivo brain model of amyloid over-expression. Specific Aim 1: Optimal in vivo vectors for gene therapy: Comparison of AAV and Lentivirus for amount, duration and safety of gene expression Specific Aim 2: Determine whether in vivo NGF transfer will prevent cholinergic neuronal degeneration and sustain gene expression for prolonged time periods. Specific Aim 3: Determine whether in vivo NGF transfer in aged rhesus monkeys will ameliorate cognitive deficits and atrophy of basal forebrain cholinergic neurons. Specific Aim 4: Develop a model for amyloid over-expression, and examine potential neural toxicity, in the young and aged primate brain.